Clinical Pharmacology & Therapeutics
August 10, 2011
Kazuya Maeda, Yasumasa Ikeda, Tomoe Fujita et al.
207 citations
Atorvastatin, a cholesterol-lowering drug, is cleared from the body by being taken up into the liver via organic anion transporting polypeptides (OATPs) and then broken down by the enzyme CYP3A4. A clinical study using a microdose cocktail given to eight healthy volunteers showed that blocking OATPs with rifampicin increased atorvastatin's exposure 12-fold, while blocking CYP3A4 with itraconazole had no effect. This demonstrates that hepatic uptake via OATPs, not metabolism by CYP3A4, is the dominant process for eliminating atorvastatin at a subtherapeutic dose.
The Journal of Clinical Pharmacology
May 19, 2011
Ichiro Ieiri, Yohei Doi, Kazuya Maeda et al.
106 citations
In 30 healthy volunteers matched for SLCO2B1 genotype, the effect of a genetic variant on the body's exposure to celiprolol depended on the dose. At a therapeutic dose (100 mg), people with two copies of the *3 variant had a lower average area under the concentration-time curve (AUC) of 775 ng·h/mL compared with 1097 ng·h/mL for those with one copy (*1/*3) and 1547 ng·h/mL for those with none (*1/*1). At a microdose (97.5 µg), these genotype differences disappeared. Dose-normalized AUC was much lower at the microdose, suggesting saturation of an efflux transporter at the therapeutic dose explains why the genetic effect only appears at that higher dose.
Nature Reviews Drug Discovery
September 8, 2020
Tal Burt, Graeme Young, Wooin Lee et al.
101 citations
Phase 0 approaches, including microdosing, are early-stage clinical trials that test very low, subtherapeutic doses of new drugs in humans to gather safety and pharmacological data before larger studies. Traditionally used to assess pharmacokinetics, these methods now also help understand a drug's mechanism of action and pharmacodynamics. Phase 0 trials can improve the selection of drug candidates for further development, making the process safer, cheaper, quicker, and more informed. While challenges like extrapolating results to therapeutic doses and managing development timelines remain, the authors suggest that phase 0 approaches should be considered for most drug development scenarios.
Advanced Drug Delivery Reviews
October 14, 2010
Yuichi Sugiyama, Shinji Yamashita
60 citations
Microdose clinical studies, which administer less than 100 μg of a test compound, allow selection of drug candidates with favorable pharmacokinetic profiles in humans while minimizing risk of harmful events. However, the low dose may produce different pharmacokinetic profiles than at therapeutic doses, and no efficacy or safety information is obtained from such studies. Combining microdose study data with physiologically based pharmacokinetic (PBPK) model analysis of in vitro metabolism, transport, and binding enables accurate prediction of therapeutic-dose pharmacokinetics. Positron emission tomography molecular imaging can further provide efficacy and safety information. Coordinating these methodologies is expected to innovate drug discovery and development.
Clinical Pharmacology & Therapeutics
June 29, 2011
Kazuya Maeda, Junichi Takano, Yasumasa Ikeda et al.
50 citations
Microdosing studies help identify early pharmacokinetic properties of drugs in humans, but nonlinearity between microdose and therapeutic dose due to saturation of metabolic enzymes and transporters is a concern. In healthy subjects, verapamil and quinidine, substrates of MDR1 and CYP3A4, showed dose-dependent pharmacokinetics. Dose-normalized AUC values increased 2.6-fold for quinidine and 2.3-fold for verapamil at therapeutic doses compared to microdoses, suggesting saturation of MDR1 and/or CYP3A4 in the small intestine causes nonlinearity.
Frontiers in Pharmacology
July 25, 2024
Yasunori Aoki, Malcom Rowland, Yuichi Sugiyama
Intra-Target Microdosing (ITM), a Phase 0 clinical approach, can engage targets at levels similar to systemically administered therapeutic doses for certain compounds, but its probability of success notably decreases when the predicted therapeutic dose exceeds 10 mg. Key factors influencing ITM success include lower dissociation constants, higher systemic clearance, and optimal receptor abundance in the target organ. Target tissues with relatively low blood flow rates and high drug clearance capacities are more conducive to successful ITM. The findings highlight the need to consider each drug's unique pharmacokinetic and pharmacodynamic properties alongside the physiological characteristics of the target tissue when determining ITM suitability.
Frontiers in Pharmacology
July 16, 2024
H. Markus Weiss, Yuichi Sugiyama, Esther van Duijn
Phase 0 microdosing—testing compounds at subtherapeutic doses in humans—enables early decisions in drug development with a reduced preclinical safety package. Its uptake has been slow despite advantages such as better decisions informed by early human data, reduced animal experiments, and access to vulnerable populations. Intratarget microdosing (ITM) enhances this approach by assessing safety or efficacy-related biomarkers beyond pharmacokinetics, including target expression via Positron Emission Tomography. The CIVO platform, an injectable device for surface-accessible tumors, can microdose up to eight drugs simultaneously and generate human pharmacodynamic data safely, improving translation over animal efficacy data.